Over the past 10 years, molecular cloning has revealed 14 serotonin subtypes that have been divided into 7 subfamilies. The large multiplicity of serotonin receptors has been suggested to be a direct result of the evolutionary age of 5-HT system. With the exception of 5-HT3 receptors which are ligand-gated ion channels, all of receptors are members of the serotonin receptor superfamily belonging to a large class of receptors linked to their effector functions via G-protein. (Gerhardt, C. C. et al., Brain Res. 746:207–219, 1997; Hoyer, D. et al., Neuropharmacol. 36;419–428, 1997).
In 1994, 5-HT6 serotonin receptors were discovered on pig nucleus caudatum and cerebellum membranes. Since then, 5-HT6 serotonin receptors have been observed in the olfactory tubercle, frontal and entorinal cortex, nucleus accumbens, striatum, hippocampus and in the molecular layer of the cerebellum. 5-HT6 serotonin receptors appear to be almost exclusively present in the brain and in 5-HT projection fields and not in the 5-HT neurons of raphe nuclei suggesting that 5-HT6 receptors probably have a postsynaptic role. It has been further discovered that 5-HT6 receptors are members of the G-protein superfamily and they are positively coupled to an adenylate cyclase second messenger system.
Serotonin binding to the 5-HT6 receptors induces an activation of the adenylate cyclase enzyme, with concomitant increase of intracellular cAMP levels. The recent discovery of 5-HT6 serotonin receptors has stimulated research into 5-HT6-selective ligands to demonstrate uniqueness of the new receptor subfamily and its own exact clinical significance. It is actually known that many psychoactive drugs (antidepressants, antipsychotics) exhibit high affinity for 5-HT6, however, without selectivity (Monsma, F. J. et al., Molecular Pharmacology 43.320–327, 1993; Roth, B. L. et al., J. Pharmacol. Exp. Ther. 268, 1403–1410; 1994) and that 5-HT6 receptors might modulate cholinergic neurotransmission in the central nervous system. Furthermore, 5-HT6 receptors displayed on GABA-containing neurons in the striatum and on glutamate-containing neurons of hippocampus have been suggested to mediate endogenous serotonin actions. Thus, ligands for 5-HT6 receptors might be useful to treat: motor disorders, depression, anxiety, mood disorders, memory disorders, Huntington's disease, Parkinson's disease and Alzheimer's disease. (Branchek, T. A. and Blackburn, T. P., Annu. Rev. Pharm. Toxicol. 40: 319–34, 2000).
5-HT7 serotonin receptors were identified in several rodent and human tissues. In rat brain, 5-HT7 receptors appear with particularly high distribution in hypothalamus, thalamus and hippocampus, while lower 5-HT7 receptor RNAm levels were found in the cerebral cortex, striatum, olfactory bulb and olfactory tubercle. The presence of 5-HT7 receptor RNAm is not limited to the brain, it has also been found in peripheral tissues (spleen, stomach, intestine, heart, coronary artery). 5-HT7 receptors are functionally coupled to adenylate cyclase enzymatic system. Pharmacological in vitro evidences demonstrate increase of endocellular cAMP levels following 5-HT7 receptor stimulation. As with 5-HT6 serotonin receptors, the clinical value of 5-HT7 receptors is not currently known (Sleight, A. J., Boess, F. G., Bourson, A., Sibley, D. R., Monsma, F. J., 1997 DN&P 10 (4):214–224). It has been suggested that 5-HT7 receptors might be involved in the mechanisms regulating blood pressure. 5-HT7 receptors' high distribution on the blood vessels and pharmacological data demonstrating vasodilatation following serotonin binding to the 5-HT7 receptors suggest utilization of 5-HT7 ligands as hypotensive agents (Martin, G. R. and Wilson, R., (1995) British J. Pharmacol. 114: 383P). Furthermore, it was previously demonstrated that 5-HT7 receptors, abundantly present in the hypothalamus, are implicated in the control of circadian rhythm of spontanieus neuronal electrical activity in the central nervous system (Lowenberg, T. N. et al., Neuron (1993) 11:449–58).
Thus, 5-HT7 ligands may be modulator agents of many processes regulated by circadian rhythm particularly sleep cycle whose desynchronization induces sleep disorders. Other evidences demonstrate that 5-HT7 receptors might be involved in the pathogenesis and treatment of depression. The observation that, 5-HT7 receptor binding sites in rat hypothalamus determine a down-regulation following chronic treatment with antidepressant Fluoxetine, has supported this therapeutic indication (Sleight, A. J. et al., Mol. Pharm. (1996), 47: 99–103). The strict classical notions of neurotransmitter disregulation hypothesis that associate depression with a deficiency of available neurotrasmitter or subresponsivity of mainly noradrenergic and/or serotoninergic receptor systems have recently been expanded to include disturbances in biological rhythm regulation. Impairment of the efficiency of rhythm maintenance or rhythm desynchronization has been suggested by many to lead to mental fatigue and depression (Goodwin F. K., Wirz-Justice A., Wehr T. A., 1982. It Costa Ragni (eds.), Typical and atypical antidepressant: Clinical pratical).
Although melatonin is generally thought to be a primary modulator of circadian functions, serotonin also plays a critical role, particularly acting on 5-HT1a, 5-HT1b, 5-HT2a, 5-HT7 subtypes in the soprachiasmatic nucleus of the hypothalamus (Van Den Pol, A. N., Dudek, F. E., (1993) Neurosciensce 56:793–811; Mullins, U. L., et al., (1999): Neuropsychopharmacology 21, (3) 352–367).
Contemporary localization of 5-HT6 and 5-HT7 receptor sites, although with different density of distribution, in brain areas (hippocampus, frontal cortex) implicated functionally in the attention and learning processes and that same ability on the part of both receptors to increase endocellular cAMP levels following their stimulation have suggested that agents binding both 5-HT6 and 5-HT7 receptor might modulate neuronal plasticity mechanism underlying the acquisition and subsequently the learning processes of an individual.
Ligands with contemporary affinity for 5-HT6 and 5-HT7 receptors might have a therapeutic use in conditions requiring an improvement in cognitive processes (Menese, A., (1999) Neurosci. Biobehav. Rev., 23 (8):1111–25).
Probable use of 5-HT7-ligands in treatment of irritable bowel disease has been suggested by recent evidence. Gastric hypomotility is thought to be one of the mechanisms underlying pathophysiological mechanism of this syndrome and remains an attractive therapeutic target. Actually a new generation of prokinetics includes 5-HT4 receptor ligands (tegaserod, prucalopride). Preliminary evidence arouses interest in research of 5-HT7 receptor ligands to be directed toward the above therapeutic target (De Ponti, F., Tonini, M., (2001) Drugs, 61 (3):317–332). In fact, the observation that 5-HT7 receptors mediate smooth muscle relaxation and 5-HT7 binding sites localization on intestine tissue should suggest therapeutic use of 5-HT7 receptor ligands.
At the present, compounds with affinity for the 5-HT6 receptor have been identified belonging to different chemical classes. For example, EP 0 815 861 and EP 0 930 302, Hoffmann-La Roche, describe sulphonamides and benzosulphonate derivatives as selective ligands for the above-mentioned receptors; WO 98/27058, SmithKline Beecham, describe carboxyamide indole derivatives as 5-HT6 receptor antagonists, whilst WO 98/27081 and WO 99/42465, SmithKline Beecham, describe, amongst others, sulphonamide derivatives, as does U.S. Pat. No. 6,187,805, Merck Sharp and Dohme; WO 00/12623, SmithKline Beecham, describes sulphonate and sulphonamidederivatives: WO 00/37452, Merck Patent, describes sulphonyloxazolylamines: WO 00/63203 and U.S. Pat. No. 6,133,287, Allelix Biopharmaceutical Inc., describe piperidinoindoles as acting as 5-HT6 antagonists.
Tryptamine derivatives are well-known for several pharmacological uses. WO 97/06140 describes their use for the treatment of pathologies correlated with melatonin disturbances; WO 97/46525 and WO 98/23587 as selective ligands of the 5-HT1D receptor and their use in the treatment of migraine; WO 97/48680 for the treatment of vasospasms; WO 98/06695 for dermatological treatments; WO 98/47868 as combined activity antagonists of various subtypes of the 5-HT1 receptor; WO 00/11619 as selective antagonists of the 5-HT2A receptor; WO 99/51576 for the treatment of nervous disorders associated with the serotoninergic system; WO 99/54301 as antibacteric agents; WO 00/37441 for the treatment of cardiovascular, ischaemic, parasitic, inflammatory, neurodegenerative diseases, myopathy and sickle-cell anemia; WO 00/78716 and WO 00/44721 as active agents on the adrenergic system.
Other tryptamine derivatives are noted for their activity against serotoninergic receptors different from 5-HT6, for example WO 95/14004, WO 95/24200, WO 96/26922, WO 96/26923, WO 97/13512, WO 99/51576, EP 1023898 and WO 00/52002.
Regarding compounds with specific activity against the 5-HT6 receptor, WO 99/47516, Slassi et. al. describes 1-acyl or 1-sulphonylindole substituted at position 3 with an alkylpyrrolidine with affinity for the 5-HT6 receptor. WO 99/65906, Allelix Biopharmaceuticals Inc. discloses bicyclic piperidines and piperazines linked to an indole residue as inhibitors of the 5-HT6 receptor.
Patent application WO 00/34242, Virginia Commonwealth University, discloses serotonin derivatives with increased affinity and selectivity for the 5-HT6 receptor. Patent application WO 00/63203, Allelix Biopharmaceuticals Inc., discloses 1-acyl or 1-sulphonylindoles, substituted at position 3 with a piperidine, having affinity for the 5-HT6 receptor.
As for the 5-HT7 receptor, WO 00/37082, Smithkline Beecham, discloses the use of 5-HT7 receptor antagonists described in WO 97/29097, WO 98/48681 and WO 97/49695 for the treatment of neuronal degenerations resulting from ischemic events; EP 0 998 923, BASF, discloses the use of 5-HT7 receptor antagonists in the prevention of ischemias, in particular infarction; WO 99/54303 and WO 98/00400, Meiji, discloses tetrahydrobenzindoles for the treatment of mental and circulatory disorders.